Abstract Messenger RNA degradation represents a critical step in the regulation of gene expression. While the major pathways and enzymes catalyzing mRNA turnover have been identified, accounting for disparate half-lives has been elusive. Recently, we have discovered that codon optimality is a major feature that contributes greatly to mRNA stability1. Codon optimality is a term to describe the fact that tRNA levels are not the same in the cell2,3. Thus is it predicted that each of the 61 codons is read by the ribosome at a slightly different rate4-7. Codons whose tRNA levels are high are termed optimal codons, while codons whose tRNA levels are low are termed non-optimal codons. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched in codons designated optimal, whereas unstable mRNAs contain predominantly non-optimal codons. Substitution of optimal codons with synonymous, non-optimal codons results in dramatic mRNA destabilization, while the converse substitution significantly increases stability. Further, we show that optimal codon content accounts for the similar stabilities observed in mRNAs encoding proteins with coordinated physiological function. We suggest that codon optimality impacts ribosome translocation, connecting the processes of translation elongation and decay. This work demonstrates that the degeneracy in the genetic code exists as a mechanism to finely tune levels of mRNAs, and ultimately, proteins through codon optimality. We will continue to investigate the influence of codon optimality on gene expression in this proposal.